HLA Class-II Associated HIV Polymorphisms Predict Escape from CD4+ T Cell Responses

Area of Science:

• Immunology
• Virology
• Computational Biology

Background:

• Antiretroviral therapy, antibodies, and CD8+ T cells exert pressure on HIV-1, driving viral escape.
• The role of CD4+ T cells in exerting selective pressure on HIV-1 evolution has been unclear.

Purpose of the Study:

• To investigate the role of CD4+ T cells in driving human immunodeficiency virus (HIV) evolution.
• To identify HIV sequence adaptations associated with HLA-II alleles and evaluate their immunogenicity.

Main Methods:

• Computational analysis of HIV gag/pol/nef sequences and HLA-II allelic data from an African cohort.
• Identification of HLA-associated HIV sequence polymorphisms (HLA-APs).
• Evaluation of epitope immunogenicity using CD8-depleted IFN-γ ELISpot assays in individuals with chronic and acute HIV infection.

Main Results:

• 29 HLA-II associated HIV sequence adaptations (HLA-APs) were identified.
• CD4+ T cell responses to adapted epitopes (AE) were lower than to non-adapted epitopes (NAE) in both controllers and non-controllers.
• Individuals with acute HIV infection showed poor immunogenicity to AE, with longitudinal data confirming CD4+ T cell escape mutations.

Conclusions:

• CD4+ T cells are active participants in driving HIV evolution, exerting selective pressure through escape mutations.
• HLA-associated polymorphisms can be used to identify biologically relevant CD4+ T cell epitopes.
• Understanding CD4+ T cell-mediated immune responses is critical for HIV control strategies.